Joachim Nielsen

University of Southern Denmark | SDU · Institute of Sports Science and Clinical Biomechanics

Decline in mitochondrial function is linked to decreased muscle mass and strength in conditions like sarcopenia and type 2 diabetes. Despite therapeutic opportunities, there is limited and equivocal data regarding molecular cues controlling muscle mitochondrial plasticity. Here we uncovered that the mitochondrial mRNA-stabilizing protein SLIRP, in...

Endurance exercise performance is associated with a well-developed skeletal muscle mitochondrial network, which is composed of subsarcolemmal mitochondria interconnected with intermyofibrillar mitochondria bending around the myofibrils. High-altitude exposure is typically incorporated in elite sport training regimens, but little is known about how...

This Commentary discusses the implications of a recent JGP study (Ríos et al. https://www.doi.org/10.1085/jgp.202413595) demonstrating an AI model to quantify glycogen granules.

Aim: The present study aimed to investigate the effects of a single bout of resistance exercise on mitophagy in human skeletal muscle (SkM). Methods: Eight healthy men were recruited to complete an acute bout of one-leg resistance exercise. SkM biopsies were obtained one hour after exercise in the resting leg (Rest-leg) and the contracting leg (Ex...

In skeletal muscle, glycogen particles are distributed both within and between myofibrils, as well as just beneath the sarcolemma. Their precise localisation may influence their degradation rate. Here, we investigated how exercise at different intensities and durations (1‐ and 15‐min maximal exercise) with known variations in glycogenolytic rate an...

Purpose This study investigated the effects of prolonged intermittent cycling exercise on peak power output (PPO) and 6-min time-trial (6 min-TT) performance in elite and professional road cyclists. Moreover, the study aimed to determine whether changes in performance in the fatigued state could be predicted from substrate utilization during exerci...

Decline in mitochondrial function associates with decreased muscle mass and strength in multiple conditions, including sarcopenia and type 2 diabetes. Optimal treatment could include improving mitochondrial function, however, there are limited and equivocal data regarding the molecular cues controlling muscle mitochondrial plasticity. Here we uncov...

During submaximal exercise, there is a heterogeneous recruitment of skeletal muscle fibers, with an ensuing heterogeneous depletion of muscle glycogen both within and between fiber types. Here, we show that the mean (95% CI) mitochondrial volume as a percentage of fiber volume of non‐glycogen‐depleted fibers was 2 (−10:6), 5 (−21:11), and 12 (−21:−...

The impact of training status and sex on intrinsic skeletal muscle mitochondrial respiratory capacity remains unclear. We examined this by analysing human skeletal muscle mitochondrial respiration relative to mitochondrial volume and cristae density across training statuses and sexes. Mitochondrial cristae density was estimated in skeletal muscle b...

Purpose O 2 -transport and endurance exercise performance are greatly influenced by hemoglobin mass (Hb mass ), which largely depends on lean body mass (LBM). This study investigated the effects of 8 weeks with 3 weekly sessions of conventional (3-SET: 3x10 reps) or high-volume strength training (10-SET: 5-10x10 reps) on LBM, Hb mass , muscle stren...

and graphical abstract The decline in mitochondrial function is associated with decreased muscle mass and strength in multiple conditions, including sarcopenia, type 2 diabetes, and cancer. Treatment of these diseases could include improving mitochondrial function, however, there are limited and equivocal data regarding the molecular cues that cont...

Intramuscular lipids are stored as subsarcolemmal or intramyofibrillar droplets with potential diverse roles in energy metabolism. We examined intramuscular lipid utilization through transmission electron microscopy during repeated high-intensity intermittent exercise, an aspect that is hitherto unexplored. Seventeen moderately-to-well-trained male...

Distinct subcellular pools of glycogen particles exist within skeletal muscle fibres, distributed both within and between myofibrils and can be found in proximity to, or at a distance from mitochondria. Their precise localisation may influence their degradation rate and role in muscle function. Here, we investigated how exercise at different intens...

The molecular events governing skeletal muscle glucose uptake have pharmacological potential for managing insulin resistance in conditions such as obesity, diabetes, and cancer. With no current pharmacological treatments to target skeletal muscle insulin sensitivity, there is an unmet need to identify the molecular mechanisms that control insulin s...

It has recently been established that myosin, the molecular motor protein, is able to exist in two conformations in relaxed skeletal muscle. These conformations are known as the super-relaxed (SRX) and disordered-relaxed (DRX) states and are finely balanced to optimize ATP consumption and skeletal muscle metabolism. Indeed, SRX myosins are thought...

Mitochondria are the cellular organelles responsible for resynthesising the majority of ATP. In skeletal muscle, there is an increased ATP turnover during resistance exercise to sustain the energetic demands of muscle contraction. Despite this, little is known regarding the mitochondrial characteristics of chronically strength‐trained individuals a...

Intramuscular lipid droplets (LDs) and mitochondria are essential organelles in cellular communication and metabolism, supporting local energy demands during muscle contractions. While insulin resistance impacts cellular functions and systems within the skeletal muscle, it remains unclear whether the interaction of LDs and mitochondria is affected...

Performance in short-duration sports is highly dependent on muscle glycogen, but the total degradation is only moderate and considering the water-binding property of glycogen, unnecessary storing of glycogen may cause an unfavorable increase in body mass. To investigate this, we determined the effect of manipulating dietary carbohydrates (CHO) on m...

Mitochondria are the cellular organelles responsible for resynthesising the majority of ATP. In skeletal muscle, there is an increased ATP turnover during resistance exercise to sustain the energetic demands of muscle contraction. Despite this, little is known regarding the mitochondrial characteristics of chronically strength-trained individuals a...

Excessive storage of lipid droplets (LDs) in skeletal muscles is a hallmark of type 2 diabetes. However, LD morphology displays a high degree of subcellular heterogeneity and varies between single muscle fibers, which impedes the current understanding of lipid-induced insulin resistance. Using quantitative transmission electron microscopy (TEM), we...

It has recently been established that myosin, the molecular motor protein, is able to exist in two conformations in relaxed skeletal muscle. These conformations are known as super-relaxed (SRX) and disordered-relaxed (DRX) states and are finely balanced to optimize skeletal muscle metabo-lism. Indeed, SRX myosins are thought to have a 10-fold reduc...

Glycogen particles are situated in key areas of the muscle cell in the vicinity of the main energy‐consumption sites and may be utilised heterogeneously dependent on the nature of the metabolic demands. The present study aimed to investigate the time course of fibre type‐specific utilisation of muscle glycogen in three distinct subcellular fraction...

Purpose: We investigated the coupling between muscle glycogen content and localization and high-intensity exercise performance using a randomized, placebo-controlled, parallel-group design with emphasis on single-fiber subcellular glycogen concentrations and sarcoplasmic reticulum Ca2+ kinetics. Methods: Eighteen well-trained participants perfor...

Glycogen is a key energy substrate in excitable tissue, including in skeletal muscle fibers where it also contributes to local energy production. Transmission electron microscopy imaging has revealed the existence of a heterogenic subcellular distribution of three distinct glycogen pools in skeletal muscle, which are thought to reflect the requirem...

Muscle glycogen is an important fuel source for contracting skeletal muscle, and it is well documented that exercise performance is impaired when the muscle’s stores of glycogen are exhausted. The role of carbohydrate (CHO) availability on exercise performance has been known for more than a century, while the specific role of muscle glycogen for mu...

With the use of transmission electron microscopy, high-resolution images of fixed samples containing individual muscle fibers can be obtained. This enables quantifications of ultrastructural aspects such as volume fractions, surface area to volume ratios, morphometry, and physical contact sites of different subcellular structures. In the 1970s, a p...

Glycogen is a key energy substrate in excitable tissue and especially in skeletal muscle fibers it contributes with a substantial, but also local energy production. A heterogenic subcellular distribution of three distinct glycogen pools in skeletal muscle is proved by transmission electron microscopy (TEM), which is thought to represent the require...

Aim: The maintenance of healthy and functional mitochondria is the result of a complex mitochondrial turnover and herein quality-control program which includes both mitochondrial biogenesis and autophagy of mitochondria. The aim of this study was to examine the effect of an intensified training load on skeletal muscle mitochondrial quality control...

Objective NAD⁺ is a co-factor and substrate for enzymes maintaining energy homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT) controls NAD⁺ synthesis, and in skeletal muscle, NAD⁺ is important for muscle integrity. However, the underlying molecular mechanisms by which NAD⁺ synthesis affects muscle health remain poorly understood. Thus, the...

Objective: To explore the relationship between the contents of subcellular localization specific mitochondria (mitochondria between myofibrils, mitochondria under the muscle membrane, total mitochondria) and different muscle fiber types, and the effect of short-term diet intervention on the content of subcellular localization specific mitochondria...

Ischaemic preconditioning (IPC) protects against myocardial ischaemia–reperfusion injury. The metabolic and ionic effects of IPC remain to be clarified in detail. We aimed to investigate the effect of IPC (2 times 5 min ischaemia) on the subcellular distribution of glycogen and Ca2+-uptake and leakiness by the sarcoplasmic reticulum (SR) in respons...

New findings: What is the central question of this study? Glycogen supercompensation following glycogen-depleting exercise can be achieved by consuming a carbohydrate-enriched diet, but the associated effects on the size, number and localization of intramuscular glycogen particles is unknown. What is the main finding and its importance? Using tran...

Aim: Glycogen particles are found in different subcellular localizations, which are utilized heterogeneously in different fibre types during endurance exercise. Although resistance exercise typically involves only a moderate use of mixed muscle glycogen, the hypothesis of the present study was that high-volume heavy-load resistance exercise would...

Key points When muscle biopsies first began to be used routinely in research on exercise physiology five decades ago, it soon become clear that the muscle content of glycogen is an important determinant of exercise performance. Glycogen particles are stored in distinct pools within the muscles, but the role of each pool during exercise and how this...

San-Millán and colleagues [...]

Little is presently known about the effects of acute high-intensity exercise or training on release and uptake of Ca²⁺ by the sarcoplasmic reticulum (SR). The aims here were to characterize this regulation in highly trained athletes following (1) repeated bouts of high-intensity exercise and (2) a period of endurance training including high-intensi...

Little is presently known about the effects of acute high-intensity exercise or training on release and uptake of Ca 2+ by the sarcoplasmic reticulum (SR). The aims here were to characterize this regulation in highly trained athletes following (1) repeated bouts of high-intensity exercise and (2) a period of endurance training including high-intens...

Mitochondrial dysfunction has been implicated as a central mechanism in the metabolic myopathy accompanying critical limb ischemia (CLI). However, whether mitochondrial dysfunction is directly related to lower extremity ischemia and the structural and molecular mechanisms underpinning mitochondrial dysfunction in CLI patients is not understood. Her...

Key points Muscle glycogen content is associated with muscle function, but the physiological link between the two is poorly understood. This study investigated the effects of inhibiting glycogenolysis, while maintaining high overall energy status, on different aspects of muscle function. We demonstrate here that Na⁺,K⁺‐ATPase activity depends on gl...

As one of the most physically demanding sports in the Olympic Games, cross-country skiing poses considerable challenges with respect to both force generation and endurance during the combined upper- and lower-body effort of varying intensity and duration. The isoforms of myosin in skeletal muscle have long been considered not only to define the con...

This study compared the effects of moderate-intensity endurance training and high-intensity interval training on fiber type-specific subcellular volumetric content and morphology of lipid droplets and mitochondria in skeletal muscles of type 2 diabetic patients. Sixteen sedentary type 2 diabetic patients (57{plus minus}7 years old) were randomized...

Low testosterone levels in aging men are associated with insulin resistance. Mitochondrial dysfunction, changes in glycogen metabolism, and lipid accumulation are linked to insulin resistance in skeletal muscle. In this randomized, double‐blinded, placebo‐controlled study, we investigated the effects of six‐month testosterone replacement therapy (T...

Superfast muscles (SFMs) are extremely fast synchronous muscles capable of contraction rates up to 250 Hz, enabling precise motor execution at the millisecond time scale. SFM phenotypes have been discovered in most major vertebrate lineages, but it remains unknown whether all SFMs share excitation-contraction coupling pathway adaptations for speed,...

In skeletal muscle, an accumulation of lipid droplets (LDs) in the subsarcolemmal space is associated with insulin resistance, but the underlying mechanism is not clear. We aimed to investigate how the size, number and location of LDs are associated with insulin sensitivity and muscle fiber types, and are regulated by aerobic training and treatment...

Key points: Although lipid droplets in skeletal muscle are an important energy source during endurance exercise, our understanding of lipid metabolism in this context remains incomplete. Using transmission electron microscopy, two distinct subcellular pools of lipid droplets can be observed in skeletal muscle - one beneath the sarcolemma and the o...

Superfast muscles (SFM) are extremely fast synchronous muscles capable of contraction rates up to 250 Hz, enabling precise motor execution at the millisecond time scale. To allow such speed, the archetypal SFM, found in the toadfish swimbladder, has hallmark structural and kinetic adaptations at each step of the conserved excitation-contraction cou...

Key points: In human skeletal muscles, the current view is that the capacity for mitochondrial energy production, and thus endurance capacity, is set by the mitochondria volume. However, increasing the mitochondrial inner membrane surface comprises an alternative mechanism for increasing the energy production capacity. In the present study, we sho...

Key points: Glycogen is stored in local spatially distinct compartments within skeletal muscle fibres and is the main energy source during supramaximal exercise. Using quantitative electron microscopy, we show that supramaximal exercise induces a differential depletion of glycogen from these compartments and also demonstrate how this varies with f...

Objectives: Most cell culture studies have been performed at atmospheric oxygen tension of 21%, however the physiological oxygen tension is much lower and is a factor that may affect skeletal muscle myoblasts. In this study we have compared activation of G0 arrested myoblasts in 21% O2 and in 1% O2 in order to see how oxygen tension affects activa...

Expression of MYOG in G0 arrested, proliferating and differentiated human myoblasts. A very low expression of MYOG gene is detected in G0 arrested and proliferating myoblast, however the expression is more than 600-fold increased in differentiated cells. (TIF)

The importance of glycogen, as a fuel during exercise, is a fundamental concept in exercise physiology. The use of electron microscopy has revealed that glycogen is not evenly distributed in skeletal muscle fibers, but rather localized in distinct pools. In this review, we present the available evidence regarding the subcellular localization of gly...

Unaccustomed eccentric exercise is accompanied by muscle damage and impaired glucose uptake and glycogen synthesis during subsequent recovery. Recently, it was shown that the role and regulation of glycogen in skeletal muscle are dependent on its subcellular localization, and that glycogen synthesis, as described by the product of glycogen particle...

Key points Muscle glycogen (the storage form of glucose) is consumed during muscle work and the depletion of glycogen is thought to be a main contributor to muscle fatigue. In this study, we used a novel approach to first measure fatigue‐induced reductions in force and tetanic Ca ²⁺ in isolated single mouse muscle fibres following repeated contract...

Introduction Intramyocellular lipid (IMCL) content (Schrauwen-Hinderling et al. 2003) and fat oxidation during exercise (Helge 2010) has been reported to be lower in arm compared with leg muscles, and it has been argued to be due to lower training status in the arm than in the leg muscle of the study populations (Helge 2010). The aim of the present...

Studies performed already in the beginning of the last century revealed the importance of carbohydrate as a fuel during exercise and the importance of muscle glycogen on performance has subsequently been confirmed in numerous studies. However, the link between glycogen depletion and impaired muscle function during fatigue is not well understood and...

Glucose is stored in skeletal muscle fibers as glycogen, a branched-chain polymer observed in electron microscopy images as roughly spherical particles (known as β-particles of 10–45 nm in diameter), which are distributed in distinct localizations within the myofibers and are physically associated with metabolic and scaffolding proteins. Although t...

Key points Several biochemical measures of mitochondrial components are used as biomarkers of mitochondrial content and muscle oxidative capacity. However, no studies have validated these surrogates against a morphological measure of mitochondrial content in human subjects. The most commonly used markers (citrate synthase activity, cardiolipin cont...

Whole muscle glycogen levels remain low for a prolonged period following a soccer match. The present study was conducted to investigate how this relates to glycogen content and particle size in distinct subcellular localizations. Seven high-level male soccer players had a vastus lateralis muscle biopsy collected immediately after and 24, 48, 72 and...

Although glycogen is known to be heterogeneously distributed within skeletal muscle cells, there is presently little information available about the role of fibre types, utilization and resynthesis during and after exercise with respect to glycogen localization. Here, we tested the hypothesis that utilization of glycogen with different subcellular...

The aim of this study was to examine maximal voluntary knee-extensor contraction force (MVC force), sarcoplasmic reticulum (SR) function and muscle glycogen levels in the days after a high-level soccer game when players ingested an optimised diet. Seven high-level male soccer players had a vastus lateralis muscle biopsy and a blood sample collected...

Non‐technical summary Glucose is stored as glycogen in skeletal muscle. The importance of glycogen as a fuel during exercise has been recognized since the 1960s; however, little is known about the precise mechanism that relates skeletal muscle glycogen to muscle fatigue. We show that low muscle glycogen is associated with an impairment of muscle ab...